Our HIV vaccine approach is based on initial immunization with a replicating adenovirus (Ad) vector carrying an HIV gene(s) followed by a booster immunization with an HIV envelope protein. The Ad-HIV vaccine replicates in epithelial cells that line mucosal inductive sites, thus eliciting strong, persistent cellular immunity at mucosal effector sites as well as in the blood. We have shown that initial immunizations with an Ad-HIV vaccine also stimulates production of anti-HIV antibodies. Together, the regimen induces strong and durable protective responses. We have demonstrated that administration of Ad-HIV vaccine to the upper respiratory tract as well as to the gut (by oral immunization) elicits memory T cells that possess "homing receptors" leading them to traffic to the intestine, a prime site of HIV infection. Thus the vaccine approach elicits cellular immunity at a location critical for preventing or controlling HIV infection. Investigation of combination vaccine approaches using HIV DNA vaccines combined with cytokine adjuvants followed by Ad-HIV vaccine and envelope protein boosting showed them to be immunogenic. The study highlighted several areas that could be optimized for greater protective efficacy against HIV infection. A pre-clinical study in cynomolgus macaques of Mauritian origin identified MHC class I haplotypes associated with natural protection against challenge with a simian immunodeficiency virus (SIV)-HIV chimeric virus (SHIV). These results will enable better design of vaccine studies in this animal model. Further, investigation of such natural host defense mechanisms may suggest new avenues to be exploited for preventive HIV strategies.